The noradrenergic and dopaminereic neurons provide an orderly pattern of innervation to the cerebral cortex that reflects the laminar organization of the cortex. These catecholaminergic terminals in the cerebral cortex are a likely site of action of several psychotropic medications. However, the factors that determine the synaptic circuitry of the catecholaminergic afferents in cortex are poorly understood at present. The goals of this proposal are: 1) to determine the role of cerebral cortical neurons in regulating the density and distribution of noradrenergic and dopaminergic afferents and 2) to explore the functional significance of the disruption of normal pattern of catecholaminergic innervation in cortex. To selectively ablate the neurons intrinsic to the cortex, rat fetuses will be treated with the alkylating agent, methylaxozymethanol (MAM), which kills cells that are dividing; treatments with MAM will be timed for the period when individual cortical laminae are formed in the lateral cortex (a noradrenergic terminal field) and in the frontal cortex (noradrenergic and dopaminergic terminal fields). The effects of these lesions will be determined in adulthood and during development by a combination of neurochemical and neuroanatomic methods. Alterations in catecholaminergic innervation will be quantified by measurement of presynaptic neurochemical markers for these neurons; neurochemical markers for cortical cholinergic and GABAergic neurons will also be assayed. Alterations of cortical organization will be assessed in Nissl-stained sections; distribution of noradrenergic fibers will be visualized by immunocytochemical localization of dopamine-beta-hydroxylase and of dopaminergic fibers by immunocytochemical localization of tyrosine hydroxylase with homologous primary antisera. The effects of aberrant patterns of catecholaminergic innervation on their function will be explored by measuring beta-receptors and norepinephrine turn-over in lateral cortex and by measuring dopamine receptors, dopamine turnover and its response to neuroleptics in frontal cortex.